Lymphedema Review

8/11/2019 Lymphedema Review

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REVIEW

Lymphedema

Stanley G. Rockson, MD

Lymphedema is a set of pathologic conditions that are charac-

terized by the regional accumulation of excessive amounts of

interstitial protein-rich fluid. These occur as a result of an im-

balance between the demand for lymphatic flow and the capac-

ity of the lymphatic circulation. Lymphedema can result from

either primary or acquired (secondary) disorders. In this

review, the pathophysiology, classification, natural history,

differential diagnosis, and treatment of lymphedema are

discussed. Am J Med. 2001;110:288295. 2001 by Excerpta

Medica, Inc.

L

ymphedema is the general term for a set of patho-

logic conditions in which there is excessive, re-

gional interstitial accumulation of protein-rich

fluid. It can be either a primary or acquired (secondary)condition. Lymphedema usually involves abnormalities

in the regional lymphatic drainage of the extremities (ei-ther upper or lower,or both),although visceral lymphatic

abnormalities can also occur. Generalized developmentalinsufficiency of the lymphatic circulation is not compat-

ible with life (1).

In addition to thechronic changes in thesize and struc-ture of the subcutaneous and integumentary structures,

lymphedema may have a substantial effect on quality of

life and the perception of well-being (2). Patients withlymphedema manifest anxiety, depression, adjustment

problems, and difficulty in vocational, domestic, social,and sexual domains (35). Among women who developpostmastectomy lymphedema, psychological factors may

reduce compliance with available treatments (6,7).

PATHOPHYSIOLOGY OF LYMPHEDEMA

In contrast with venous edema, in which enhanced cap-

illary pressure can indirectly stimulate lymph produc-tion, lymphedema is caused by a reduction in lymphatic

transport. Several anatomic problems can lead to lym-

phatic stasis, including lymphatic hypoplasia and func-tional insufficiency or absence of lymphatic valves (8).

Some patients may have an impairment in the intrinsiccontractility of the lymphangion (the segmentally con-

tracting, functional vascular unit of the lymphatic circu-

lation) (8). Secondary lymphedema, which is much more

common than the primary form, can develop as a conse-

quence of any surgical, traumatic, inflammatory, or neo-

plastic disruption or obstruction of lymphatic pathways.

Much of the current understanding of the pathophys-

iology of lymphedema derives from the experimental

work of Olszewski (9) in dogs. In this experimental

model, mechanical interruption of lymph vessels of the

limb wassufficient to producelymphedema after a period

of months to years. Before overt edema occurred, marked

lymphangiographic changes were observed in the ab-

sence of detectable accumulation of interstitial fluid.

Eventually, lymph collectors became fibrotic and lost

their normal permeability. In addition, electron micro-graphs of skin lymph capillaries disclosed permanent in-

competence of the interendothelial junctions. In contrast

to the pattern observed in other edematous states that

occasion venous hypertension, like congestive heart fail-

ure and thrombotic venous disorders, the advent of

chronic lymphedema in these limbs was not accompa-

nied by the lymphatic hypertension that might otherwise

have been theoretically predicted.

Once established, lymphatic stasis fosters the accumu-

lation of protein and cellular metabolites, such as macro-

molecular protein and hyaluronian, within the extracel-

lularspace.Impaired lymphatic transport produces accu-mulation of both macromolecular protein and of

hyaluronian (10). This is followed by an increase in the

tissue colloid osmotic pressure, which leads to water ac-

cumulation and increased interstitial hydraulic pressure.

Chronic lymph stasis often produces an increase in the

number of fibroblasts, adipocytes, and keratinocytes in

the edematous tissues. Mononuclear cells (chiefly macro-

phages) often demarcate the chronic inflammatory re-

sponse (11,12). In most patients, there is an increase in

collagen deposition, with adipose and connective tissue

overgrowth in the edematous skin and subcutaneous tis-

sues (13). Histopathologic findings in chronic lymphed-

From the Division of Cardiovascular Medicine, Stanford UniversitySchool of Medicine, Falk Cardiovascular Research Center, Stanford,California.

Requests for reprints should be addressed to Stanley G. Rockson,MD, Division of Cardiovascular Medicine, Stanford University Schoolof Medicine, Falk Cardiovascular Research Center, Stanford, California94305.

Manuscript submitted January 3, 2000, and accepted in revised form

November 9, 2000.

288 2001 by Excerpta Medica, Inc. 0002-9343/01/$see front matterAll rights reserved. PII S0002-9343(00)00727-0


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ema include thickening of the basement membrane of

lymphatic vessels, fragmentation and degeneration ofelastic fibers, increased numbers of fibroblasts and in-

flammatory cells, and increased amounts of ground sub-

stance and pathological collagen fibers (14). Ultimately,these processes lead to progressive subcutaneous fibrosis.

CLASSIFICATION OF LYMPHEDEMA

The simplest classification of lymphedema relies upon adifferentiation between primary and secondary causes

(15). Primary lymphedemas are often classified accord-ing to the age at which the edema first appeared. Congen-

ital lymphedema is apparent at birth or becomes recog-

nized withinthe first 2 years of life. Lymphedema praecoxis most commonly detected at the time of puberty, but

may appear as late as the third decade of life. Lymphed-

ema tarda typically appears after age 35 years. Recent ad-vances within the genetic investigation of hereditary

lymphedemas have permitted the identification of possi-

ble candidate genes for lymphedema-distachiasis (16).Linkage analysis of family cohorts with cholestasis-

lymphedema syndrome has similarly resulted in success-ful chromosomal mapping of the disease locus (17). Ge-

netic mapping of the autosomal dominant form of hered-

itary primary lymphedema (Milroys disease) (18)suggests that the disease can be ascribed to a mutation

that inactivates the VEGFR3 tyrosine kinase signaling

mechanism that is felt to be specific to lymphatic vessels

(19).In congenital lymphedema, the swelling can involve

only a single lower extremity, but edema of multiple

limbs, the genitalia, and even the face can be seen. Bilat-

eral leg swelling and involvement of the entire lower ex-tremity is more likely in congenital cases than in other

forms of primary lymphedema (20).

When cases of congenital lymphedema cluster in fam-ilies, an autosomal dominant pattern of transmission is

most frequently described.However, isolated instancesof

lymphedema are much more common (21). There is astrong association between intrauterine and congenital

lymphatic dysfunction and several heritable chromo-somal abnormalities (15).

Lymphedema praecox, the most common form of pri-

mary lymphedema, is responsible for as many as 94% ofthe cases in large reported series. The estimated 10:1 ratio

of females to males suggests that estrogenic hormones are

involved (21). The edema is usually unilateral and is lim-ited to the foot and calf in the majority of patients (21).

Lymphedema tarda is relatively uncommon, and ac-

counts for fewer than 10% of cases of primary lymphed-ema.

An alternative classification for primary lymphedema

relies upon morphologic characteristics (20). Distal hyp-

oplasia of the lymphatics is typically associated with bi-

lateral peripheral edema of the lower extremities. There isusually a family history of similar symptoms, a female

predominance, and a tendency for indolent progression.

When isolated proximal obstructive hypoplasia is ob-served, clinical involvement of the entire limb is more

likely, usually accompanied by relentless worseningof theedema. Patients who have unilateral edema involving theentire lower extremity are likely to have lymphatic hyper-

plasia with megalymphatics, although this syndrome is

uncommon.Secondary lymphedema develops after disruption or

obstruction of lymphatic pathways by other disease pro-cesses, or as a consequence of surgery or radiotherapy.

Secondary lymphedema is much more common than the

primary form. Edema of the arm after axillary lymphnode dissection is probably the most common cause of

lymphedema in the United States (22), although itsglobal

incidence is overshadowed by filariasis, which affectsmore than 90 million people (23).

The reported incidence of edema after mastectomy

varies substantially, from 6% to 80% among publishedseries (22). Differences in the incidence estimates may

reflect variations in the definition of edema. A recentlypublished series suggests that, with up to 13 years of

follow-up, a 14% late incidence of postmastectomy

lymphedema can be expected in surgically treated pa-tients with adjuvant postoperative irradiation (24). Fur-

thermore, in a second recent series, 21 of 110 patients

treated with breast-conserving techniques also developed

chronic postsurgical arm swelling (25). Thus, despite im-provements in surgical and radiotherapeutic techniques,lymphedematous complications cannot be obviated and

are, in fact, not uncommon (26,27). Edema of the leg may

occur after pelvic or genital cancer surgeries, particularlywhen there has been inguinal and pelvic lymph node dis-

section or irradiation. Its reported frequency varies be-

tween 1% and 47% (28,29). Pelvic irradiation increasesthe frequency of leg lymphedema after cancer surgery

(30).

NATURAL HISTORY OF LYMPHEDEMA

The natural history of lymphedema is uncertain, partic-

ularly as it maybe asymptomatic. Forexample, as late as 3years after radical mastectomy and axillary node dissec-

tion, more than 20% of women remain free of any clinical

evidence of lymphatic impairment, despite the extensiveiatrogenic destruction of the lymphatic architecture in

these patients (31,32). Similarly, in many forms of pri-

mary lymphedema, there may be a protracted phase ofapparently normal lymphatic function, despite an inher-

ited anatomic or functional disturbance of this microcir-

culation. This latent phase of lymphedema may represent

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a balance between the existing increased lymph load anda reduced outflow capacity (32). Lymphedema may be-come manifest when compensatory mechanisms, which

may include lymphatic regeneration, become inadequate

to withstand the requirement for lymphatic flow.The precipitating factors for the appearance of overt

lymphedema are not known (33). At the onset of clinical

lymphedema, swelling of the involved extremity is typi-cally described as puffy, and the disturbance may be in-

termittent. With chronicity, the involved structures de-velop the characteristic features of induration and fibro-

sis (13), which may be substantial (Figure 1).

In many patients, the maximal increase in girth of theinvolved limb is determined within the first year after

onset, unless there are supervening complications like re-

current cellulitis. The propensity to recurrent soft-tissueinfection is one of the most troublesome aspects of long-

standing lymphedema. Microbial growth is encouraged

by the surplus of fluid and accumulated proteins. Lym-phatic dysfunction also impairs local immune responses

(34). The impaired regional immunosurveillance oflymphedema is supported by the observed impairments

in thecutaneous immune responsesin patients with post-

mastetomy lymphedema (34). With recurrent infections,

there is progressive damage of lymphatic capillaries. In

one reported series, acute cellulitis in the arm was ob-served in 6% of patients during 42 months of surveillanceafter breast cancer therapy (35).

The clinical presentation of soft-tissue infection in

lymphedema can be variable, from very subtle exacerba-tions of lymphedema characterized by skin changes with-

out fever, to rapidly progressive soft tissue infection with

high fever and systemic toxicity. Recurrent attacks of cel-lulitis further damage the cutaneous lymphatics, worsen

the skin quality, and aggravate the edema.In very rare cases, chronic lymphedema may be com-

plicated by the local development of malignant tumors

such as lymphangiosarcomata, which can be either scle-rotic plaques or multicentric lesions with blue-tinged

nodules or bullous changes (36). Other cutaneous malig-

nancies that have been observed in association withchronic lymphedema (37) include lymphoma, mela-

noma (38), squamous cell carcinoma (39), and Kaposis

sarcoma (40).

DIAGNOSIS OF LYMPHEDEMA

In most patients with advanced lymphedema, the charac-

teristic clinical presentation and physical findings estab-

Figure 1. Severe, advanced primary lymphedema with fibrosis, hyperpigmentation, and excoriation of the skin.

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lish the diagnosis with near certainty (41). However, early

in the natural history, or with presentations of mild orintermittent swelling, it may be more difficult to distin-

guish lymphedema from other edematous states. Several

physical features distinguish lymphedema from othercauses of chronic edema of the extremities. Among these

are the classic changes of cutaneous and subcutaneousfibrosis (peau dorange), and the Stemmer sign, which isan inability to tent the skin on the dorsum of the digits of

the feet. Although the Stemmer sign has not been vali-

dated, it was initially reported to discriminate patientswith lymphedema (42). Lymphedema in the legs often

produces preferential swelling of the dorsum of the foot,as well as the characteristic blunt, squared-off appear-

ance of the digits in the involved extremity.

When the physical examination does not conclusivelysupport the diagnosis of lymphedema, additional evi-

dence may be necessary to confirm impaired lymphatic

function. Available tests include isotopic lymphoscintig-raphy, indirect and direct lymphography, lymphatic cap-

illaroscopy, magnetic resonance imaging (MRI), axial to-

mography, and ultrasonography. Direct lymphography isgenerally limited to the evaluation of candidates for lym-

phatic surgery. Isotopic lymphoscintigraphy is the mostcommonly used test and is generally considered to be the

gold standard for the diagnosis of lymphedema. A radio-

labeled macromolecular tracer (eg, sulfur colloid) is ad-ministered into the subdermal, interdigital region of the

affected limb. The lymphatic transport of the radiola-

beled macromolecule can be monitored in a semiquanti-

tative fashion with a gamma camera. Major lymphatictrunksand lymph nodes can be visualized. Typical abnor-malities in lymphedema include absent or delayed trans-

port of tracer, absent or delayed visualization of lymph

nodes, crossover filling with retrograde backflow, anddermal backflow (4345). In a series of more than 700

patients, peripheral lymphatics were visualized readily

(46). These imaging techniques can also be used to mon-itor the effects of therapy and to facilitate invasive thera-

pies for chylous reflux (the reflux of intestinal lymph to

the skin as a consequence of lymphatic valvular incom-petence) (47).

Magnetic resonance imaging and computerized tomo-graphic (CT) imaging allow the objective documentation

of structural changes attributable to lymphedema (48).

The characteristic absence of edema within the muscularcompartment helps to distinguish lymphedema radio-

graphically from other forms of edema. In addition, the

honeycomb distribution of edema within the epifascialplane, along with thickening of the skin, is characteristic

of lymphedema. The anatomic delineation of lymphatic

and nodal architecture derived from MR imaging cancomplement the functional assessment provided by lym-

phoscintigraphy (45,49).

Less commonly employed techniques include tissue

tonometry (50,51) and bioelectric impedance analysis

(5255). These techniques allow detection of small

changes in tissue turgor and mayhave utility in the detec-

tion of subclinical states of lymphatic impairment, as well

as in the serial assessment of the response to treatment.

DIFFERENTIAL DIAGNOSIS

Chronic Venous Insufficiency and PostphlebiticSyndromeThis common condition is often confused with lymphed-

ema of the legs. Its distinguishing clinical features include

aching discomfort in the lower extremities during sitting

or standing and chronic pruritus, particularly overlying

the incompetent communicating veins (56). Physical

findings include cutaneous deposits of hemosiderin,

dusky discoloration and venous engorgement with de-

pendence, cutaneous varicosities, and if advanced, ulcer-

ation of the skin.

MyxedemaThis special form of edema arises when abnormal depos-

its of mucinous substances accumulate in the skin as a

result of thyroid disease (57). Hyaluronic acid-rich pro-

tein deposition in the dermis produces edema that, in

turn, disrupts structural integrity and reduces the elastic-

ity of the skin. In thyrotoxicosis, this process is focal in the

pretibial region (58); in hypothyroidism, the myxedema

is more generalized. Myxedema is characterized by

roughening of the skin of the palms, soles, elbows andknees; brittle, uneven nails; dull, thinning hair; yellow-

orange discoloration of the skin; and reduced sweat pro-

duction. However, it may be difficult to distinguish from

lymphedema.

LipedemaThis condition affects women, or men with a feminizing

disorder. The edema is caused by the abnormal accumu-

lation of fatty substances in the subcutaneous regions,

typically between the pelvis and the ankle, with sparing of

the feet. Although the pathophysiology of this disorder is

uncertain, it does involve an excess of subcutaneous adi-pocytes with structural alterations in the small vascular

structures within the skin. Indeed, regional abnormalities

of the circulation may cause the initial accumulation of

fat in the affected regions (59). The characteristic distri-

bution, with sparing of thefeet, should suggest thecorrect

diagnosis. The absence of a Stemmers sign is an addi-

tional clue. Most often, lipedema arises within1 to 2 years

after the onset of puberty. In addition to the near lifelong

history of heavy thighs and hips, affected patients often

complain of painful swelling. In addition, there is com-

monly a propensity to bruising, perhaps a result of in-

creased fragility of capillaries within the adipose tissue.

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Malignant LymphedemaIn the United States, the leading cause of lymphedema ofboth upper and lower extremities is neoplastic disease

and related therapies. Thus, in the differential diagnosis

of new or worsening lymphedema, recurrence of cancer,leading to intrinsic or extrinsic obstruction of lymph

flow, must be considered. Malignant lymphedema oftendevelops rapidly and progresses relentlessly (60). In addi-

tion, pain, which is generally absent in benign lymphed-

ema, may be present. The malignant form of lymphed-ema tends to begin centrally. Often, the tissue is quite

firm from the outset, without the soft consistency seen in

the early stages of benign lymphedema.

LYMPHEDEMA TREATMENT

General Therapeutic MeasuresLymphedema is a chronic condition that requires lifelongattention. Meticulous attention to control of edema may

reduce the likelihood of disease progression and limit the

incidence of soft-tissue infections (41). Aggressive imple-mentation of decongestive lymphatic therapy is the

mainstay of most therapeutic recommendations(6163). This complex form of physical therapy inte-

grates meticulous skin care, massage, exercise, and use of

compressive elastic garments. Decongestive lymphatictherapy can acutely reducelimb volume as well as provide

long-term benefits owing to the acceleration of lymph

transport in the edematous limb and the dispersal of ac-

cumulated protein (63).The specialized massage technique for these patients

(manual lymphatic drainage or therapy) is intended to

enhance lymphatic contractility and to augment and re-

direct lymph flow through the nonobstructed cutaneouslymphatics. Manual lymphatic drainage should not be

confused with other forms of therapeutic massage that

have no effect on lymphatic contractility. The mild tissuecompression during manual lymphatic drainage pro-

duces better filling of the initial lymphatics and enhances

transport capacity, through the cutaneous lymphatic di-latation and development of accessory lymph collectors

(64).During the acute approach to volume reduction, non-

elastic, compressive wrappings should be applied after

each session of manual lymphatic drainage and wornduring exercise to prevent reaccumulation of fluid and to

promote lymph flow during exertion. Complete decon-

gestive physiotherapy, including manual lymphaticdrainage, compression bandaging, garments and skin

care, is an effective treatment modality for many patients

with primary and secondary lymphedema (Figure 2). In arecent series of 299 patients, with an average follow-up of

9 months, there were average reductions of 59% in upper

extremity volume, and 68% in lower extremity volume,

with maintenance of 90%of this benefit duringfollow-up

in compliant patients (65). In another, subsequent pro-

spective analysis of therapeutic responses in chronic

lymphedema, short-term decongestive lymphatic ther-

apy, when coupled with focused patient instruction in

long-term self-care, was documented to be efficacious,

with sustainable long-term therapeutic responses (66).The use of intermittent pneumatic compression with

single or multichamber pumps removes excess fluid from

the extremity and should be considered as an adjunctive

approach (41). Pneumatic compression techniques,

however, cannot clear edema fluid from the adjacent

trunk. Consequently, as fluid shifts occur during pneu-

matic compression, the root of the limb must be decom-

pressed with manual techniques. The use of any form of

compressive therapy requires a sufficient arterial blood

supply to the limb. In cases of limb ischemia, compressive

therapy, which can compromise arterial blood flow and

promote severe ischemia and necrosis, is contraindi-

cated.

The prescription of compressive garments is a neces-

sary adjunct to all other forms of lymphedema therapy.

Relatively inelastic sleeves and underwear that transmit

high-grade compression (40 to 80 mm Hg) will prevent

reaccumulation of fluid after successful decongestive

treatments. Garments must be fitted properly and re-

placed when they lose their elasticity (every 3 to 6

months).

Other treatments are under investigation. Low-level

laser therapy may be effective in postmastectomy

lymphedema; in a series of 10 patients, subjective im-

provement was accompanied by objective documenta-

tion of improved bioimpedance and reduced extracellu-

lar and intracellular fluid accumulation (67). In addition,

some promising responses have been reported after local

hyperthermia (68) and the intra-arterial injection of au-

tologous lymphocytes (69). In the latter approach, it is

postulated that regression of edema is linked to the ex-

pression of L-selectin, a lymphocyte-specific adhesion

molecule (69).

Pharmacotherapy and Diet

The reported benefit of coumarin (5,6-benzo-[a]-py-rone) in lymphedema (70) is ascribed to its stimulatory

effect upon cutaneous macrophages and, thereby, upon

local proteolysis. Coumarin also stimulates other cellular

elements of the immune system and may promote pro-

tein reabsorption. Efficacy has been demonstrated in

lymphedema of the arms and legs (70), as wellas infilarial

elephantiasis (71). A meta-analysis of 50 clinical trials

suggests that these slow-acting compounds can provide a

mean decrease in edema volume of about 55% (72).

However, coumarin administered orally may cause idio-

syncratic hepatitis. Topical coumarins are under investi-

gation; none is available for clinical use in the United

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States. There are scant, but provocative, data concerningthe therapeutic benefit of augmenting dietary flavenoids

(73). These naturally-occurring compounds, particularly

the rutin derivatives, are thought to benefit lymphedemathrough protective effects on vascular endothelium and

general improvement in the microcirculation. In addi-

tion, there is one report that suggests that dietary restric-tion of long-chain triglycerides provides some relief of

edema in these patients (74).

Surgical TherapyInvasive approaches may be necessary in patients with

unacceptable subcutaneous adipose hypertrophy and fi-brosis (7577). Two main surgical approaches have

been utilized. In excisional procedures, part or all of the

lymphedematous epifascial tissue is removed, whereasmicrosurgical interventions involve the creation of

lymphaticolymphatic, lymphaticoveno-lymphatic, lym-

phaticovenous, or lymph node-venous anastomoses(78). Although lymphaticovenous anastomosis (79,80)

and transplantation of lymph collectors have been advo-

cated (8183) for chronic lymphedema, the long-termresults of such interventions have not been uniformly en-

couraging (81,84). Debulking surgical procedures are de-

signed to remove redundant skin and subcutaneous tis-

sue (85), often with wide excision and split skin grafting

(86). The procedures do not improve lymphatic drain-

age. Other surgical techniques include treatment with

transfer of an omental pedicle (87) or interposition of a

vascular pedicle flap to serve as a lymphatic wick (88).

Surgical approaches, however, may cause further damage

to cutaneous lymphatics and may lead to skin necrosis,

papillomatosis, ulceration, fistula formation, and edema

exacerbation (75,89). Additional surgical risks include

sensorineural damage, hypertrophic scarring, ulceration,

graft necrosis, and exophytic keratosis. Nevertheless, par-

tial excision may be indicated for cases of advanced fibro-sis or frank elephantiasis.

Suction techniques may also be used to remove excess

subcutaneous tissue. Surgical liposuction of chronic

postmastectomy lymphedema has been reported to pro-

duce excellent results, with sustained reduction of excess

volume (89,90). In one series, an average long-term re-

duction of edema volume of 106% (in some patients,

there is actually surgical overcorrection so that, when

compared with thenormallimb, the therapeutic response

is actually100%) was observed in 28 patients with an

average edema volume of 1,845 mL (89). Liposuction

with long-term decongestive compression therapy re-

Figure 2. Results of intensive decongestive lymphatic physiotherapy for severe, advanced primary lymphedema (see Figure 1).

Lymphedema/Rockson



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duces edema volume more successfully than does com-

pression therapy alone. However, the volume reductionwill not be successful unless compression therapy is

maintained after the surgical intervention (91).

ACKNOWLEDGMENTThe assistance of Dr. Andrzej Szuba in the preparation of thefigures is gratefully ackowledged.

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